Breast Cancer Information Core | Significant Updates July 26, 2007Posted by ramunas in BRCA, breast cancer, cancer genetics, genetic testing, hereditary cancer, ovarian cancer.
As you may already noticed, in the beginning of this year the most comprehensive open-access online BRCA1/2 mutation database Breast Cancer Information Core (BIC) – an international collaborative effort hosted by NHGRI – added significant improvements and more are on the way:
Changes to the BIC include redesigned search tools, a field classifying the “clinical importance” of each mutation and inclusion of additional information on a subset of mutations. Expect to see additional cosmetic and content changes in the coming months.
A field of “clinical importance” is worth further in deepth analysis. There are three categories:
1. Clinically important (“Yes”):
- Based on available data, it is the opinion of the BIC steering committee that sequence change of this type interferes with gene function and results in an increased risk of cancer.
- All clinically important alleles may not confer the same degree of risk and the precise degree of risk associated with this mutation cannot be estimated.
- This sequence change may abolish some or all of the normal functions of this gene. Some alleles may produce a stable mutant mRNA or protein.
- However, many mutant alleles of this type do not produce mRNA or the encoded protein is unstable.
2. Not clinically important (“No”):
- Based on available data, it is the opinion of the BIC steering committee that this sequence change is neutral or of little clinical importance.
- Some sequence changes of this type may be associated with modest increases in cancer risk.
- Some individuals carrying this sequence change also could carry a clinically significant mutation.
- It is likely that the mRNA and protein produced by this allele generally functions similar to wild type.
- However, this protein contains multiple functional domains and some biological functions of this allele may be compromised.
- Insufficient data exist at this time to allow assessment of the clinical or functional implications of this sequence change.
- Although we attempt to update the BIC database on a regular basis, we also suggest searching the medical literature (PubMed – Google) to determine if new information is available on this sequence change.
BIC is very useful database. And those new improvements will shed some light on polymorphisms. But variants of unknown significance (VUS), which are polymorphisms of uncertain clinical importance and account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations, still could be not easy thing to interpret without functional expression studies, phylogenetic analysis and other approaches.
More than 600 mtations in BRCA1 genes and more than 450 in BRCA2 genes are reported to date. Only about 2-3 of all breast cancer cases can be attributed to inherited mutations in BRCA1/2 genes, and up till 15% of all ovarian cancer cases (10% – BRCA1, 5% – BRCA2), unselected for ethnicity [ref.]. The overall frequency of of BRCA1 gene mutation is 0,0007 – i.e. about one woman in 700 is a heterozygous carrier [ref.] and somewhat less for BRCA2. Interestingly, that irrespective of family history between 20-25% of women diagnosed with ovarian cancer between the ages of 41 and 50 will carry a BRCA1/2 mutation [ref.].